This Program Project Grant examines different aspects of the autoimmune response. The first project is that involving the laboratories of Emil Unanue, Osami Kanagawa and Michael Gross. The project is a committed attempt to isolate biochemically the peptide moiety responsible for triggering diabetogenic CD8 T cells. The project is based on the observations that CD8 T cells play an important role in autoimmune diabetogenesis. At hand we have a number of CD8 T cell clones that recognize Kd peptide from beta cells. This T cell receptors from two of these clones have been expressed as transgenes. The project is heavy of biochemical approaches that rely on state-of-the-art mass spectrometry for peptide isolation. This effort will lead to a precise biochemical establishment of the moiety or moieties that form a beta cell specific class I-peptide complex-its identification will open several possibilities for future rational peptide immunotherapy, for control of autoimmunity. Second, (Allen), using a murine model of rheumatoid arthritis, will explore the precise nature of the ligands recognized in this disease. Altered peptide ligands will be tested in vivo for their ability to inhibit disease initiation and progression. The role of the failure of central tolerance in autoimmune diseases will also be directly explored. The third project will define molecular steps in Th1 development, focusing on identifying the specific transcription factors induced by IL-12 and Stat4 that contribute to emergence and maintenance of the effector Th1 phenotype (Murphy). Knowledge of these novel pathways will provide additional opportunities to each of the projects described above, as well as for providing new potential therapeutic interventions. The strong interactions generated by this PPG plus the infrastructure developed in our Department for Immunology research represent a strong base of this current effort.